title: Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis.
abstract: Cardiac valves are essential to direct forward blood flow through the cardiac chambers efficiently. Congenital valvular defects are prevalent among newborns and can cause an immediate threat to survival as well as long-term morbidity. Valve leaflet formation is a rigorously programmed process consisting of endocardial epithelial-mesenchymal transformation (EMT), mesenchymal cell proliferation, valve elongation and remodeling. Currently, little is known about the coordination of the diverse signals that regulate endocardial cushion development and valve elongation. Here, we report that the T-box transcription factor Tbx20 is expressed in the developing endocardial cushions and valves throughout heart development. Ablation of Tbx20 in endocardial cells causes severe valve elongation defects and impaired cardiac function in mice. Our study reveals that endocardial Tbx20 is crucial for valve endocardial cell proliferation and extracellular matrix development, but is not required for initiation of EMT. Elimination of Tbx20 also causes aberrant Wnt/β-catenin signaling in the endocardial cushions. In addition, Tbx20 regulates Lef1, a key transcriptional mediator for Wnt/β-catenin signaling, in this developmental process. Our study suggests a model in which Tbx20 regulates the Wnt pathway to direct endocardial cushion maturation and valve elongation, and provides new insights into the etiology of valve defects in humans.
authors.affiliation: Department of Developmental and Regenerative Biology, The Mindich Child Health and Development Institute, and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Cai
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Nishat
authors.initials: N
authors.lastname: Sultana
authors.forename: Bingruo
authors.initials: B
authors.lastname: Wu
authors.forename: Weibin
authors.initials: W
authors.lastname: Cai
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Chen-Leng
authors.initials: CL
authors.lastname: Cai
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D054089:Endocardial Cushions / Q000196:embryology* / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology; D006351:Heart Valves / Q000196:embryology* / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D038081:Organogenesis; D011247:Pregnancy; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D020825:T-Box Domain Proteins; C486013:Tbx20 protein, mouse; D051176:beta Catenin
keywords: Cardiac valve; Heart development; Mouse; Tbx20